The psychotomimetic effects of the widely abused drug PCP (phencyclidine, "angel dust") have been associated with blockade of the N-methyl-D- aspartate (NMDA) selective subtype of glutamate receptor. PCP-like drugs bind to a site located within the NMDA-operated ion channel, and can only bind if the receptor is activated. Activation of the NMDA receptor is subject to modulation by a number of endogenous factors, including Mg2+ and the polyamines spermidine and spermine. Understanding the effects of these modulators on the activation of the NMDA receptor is crucial for the elucidation of the molecular mechanism of action of PCP-like drugs. The specific aims of this project are: i) To understand the effects of Mg2+ and polyamines on radioligand binding to the PCP site on the NMDA receptor; ii) To study the effects of Mg2+ and polyamines on the use-dependent blockade and recovery from blockade of the NMDA receptor by PCP and related drugs; iii) To determine the effects of membrane potential on the action of PCP- like drugs; and iv) To investigate the effects of Mg2+ and polyamines on the action of novel halogenated PCP-like drugs. This project will utilize a series of well established biochemical, physiological and biophysical approaches to investigate these issues, including [3H] dizocilpine binding, intracellular Ca2+ measurements and patch-clamp electrophysiology in rat cortical neurons. These studies will greatly increase the understanding of the factors that contribute to the binding of PCP and related drugs. Moreover, by identifying modulators that may increase the action of PCP and developing antagonists to these modulators, it may be possible to develop novel approaches to the acute treatment of PCP intoxication and long-term PCP abuse.